3-naphthyloxy-2-hydroxypropylamines



United States Patent This invention relates to new homocyclic compoundsand more particularly it relates to new naphthalene derivatives whichpossess fl-adrenergic blocking activity and which are therefore usefulin the treatment or prophylaxis of coronary artery disease.

According to the invention we provide naphthalene derivatives of theformula:

0.0R 11 .CHOI LOHRRNR R wherein R stands for hydrogen or an alkyl,cycloalkyl alkenyl, aralkyl or alkanoyl radical, any of Which mayoptionally be substituted, R stands for hydrogen or an alkyl,cycloalkyl, alkenyl, alkynyl or aralkyl radical, any of which mayoptionally be substituted, or R and R are joined together with theadjacent nitrogen atom to form a heterocyclic radical optionallysubstituted, wherein R R and R which may be the same or different, standfor hydrogen or alkyl radicals, and wherein the naphthalene nucleus mayoptionally bear one or more additional substituents P and Q, and theesters thereof, and the salts thereof, but excluding 1-amino-,1-n-propylamino-, l-n- ,butylamino-, 1-diethylamino-,l-di-n-propylamino-, l-diisopropylamino-, l-di-n-butylamino-,l-morpholinoand 1-piperidino-3-(l-naphthoxy)-2-propanol, andl-ethylamino-, 1-dimethylamino-, 1-diethylamino, l-morpholinoand1-piperidino-3-(Z-naphthoxy)-2-propanol, and 1-(1-chloro-2-naphthoxy)-3-piperidino-2-propanol, and the esters thereof, andthe salts thereof.

A preferred group of compounds of the invention comprises those of thesaid naphthalene derivatives wherein R R R and R stand for hydrogen, Rhas the meaning stated above, and wherein the naphthalene nucleus mayoptionally bear one or more additional substituents, and the estersthereof, and the salts thereof, but excluding 1-amino-,1-n-propylaminoand l-n-butylamino-3-(lnaphthoxy)-2-propanol, and1-ethylamino-3-(2-naphthoxy)-2-propanol, and the esters thereof, and thesalts thereof.

As a suitable value for R there may be mentioned,

for example, an alkyl or hydroxyalkyl radical of not more than 5 carbonatoms, for example the methyl ethyl, sbutyl or Z-hydroxyethyl radical,or an aralkyl radical of not more than carbon atoms, for example thebenzyl radical, or an alkanoyl radical of not more than 6 carbon atoms,for example the acetyl radical.

As a suitable value for R there may be mentioned, for example, abranched chain alkyl radical of not more than 20 carbon atoms, forexample the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,s-butyl, t-butyl, 1- methyloctyl or l-methylhexadecyl radical, or analkyl radical of not more than 20 carbon atoms bearing one or morehydroxy radicals i.e. hydroxy-branched-chain-alkyl, or substituted aminoradicals, for example alkylamino, dialkylamino or heterocyclic radicals,for example alkylamino or dialkylamino radicals of not more than 6carbon atoms or heterocyclic radicals of not more than 6 ring atoms, forexample the dimethylamino or morpholino ice radical, or alkoxy radicals,for example alkoxy radicals of not more than 5 carbon atoms, for examplethe methoxy or n-propoxy radical, or alkoxyalkoxy radicals, for examplealkoxyalkoxy radicals of not more than 10 carbon atoms, for example the2-n-butoxyethoxy radical, or aryloxy radicals, optionally substituted,for example aryloxy radicals of not more than 10 carbon atoms,optionally substituted, for example the 4-chlorophenoxy or2,4-dichlorophenoxy radical. Alternatively, R may stand for an aralkylradical of not more than 15 carbon atoms, optionally substituted with,for example, one or more alkoxy radicals, for example alkoxy radicals ofnot more than 5 carbon atoms, for example the methoxy radical. Thus,specific values for R when it stands for a substituted alkyl radical ora substituted or unsubstituted aralkyl radical are, for example, the

2-hydroxyethyl, Z-hydroxy-l-methylethyl, Z-hydroxy-l,l-dimethylethyl,2-n-propoxyethyl, B-methoxypropyl, 2-(Z-n-butoxyethoxy)-ethyl,3-morpholinopropyl,

3 -dimethylaminopropyl,

2- (4-chlorophenoxy -ethyl,

2- (2,4-dichlorophenoxy) -ethyl,

benzyl,

l-methyl-2-phenylethyl, l-methyl-3-phenylpropyl, 1,1-dimethyl-3-phenylpropyl, 4-methoxybenzyl, 3-(4-methoxyphenyl)-l-methylpropyl or 2-3,4-dimethoxyphenyl) -ethyl radical.

Alternatively, R may stand for a cycloalkyl, alkenyl or alkynyl radicalof not more than 10 carbon atoms, for

example the cyclopentyl, allyl or l-rnethyl-Z-propynyl radical.

As a suitable value for the group --NR R when its stands for aheterocyclic radical there may be mentioned, for example, a 5- or6-membered nitrogen-containing heterocyclic radical, optionallysubstituted, for example a pyrrolidino, piperidino or morpholinoradical, any of which may optionally be substituted by one or more alkylradicals of not more than 5 carbon atoms, for example the methylradical.

As a suitable value for R R or R when it stands for an alkyl radicalthere may be mentioned, for example, an alkyl radical of not more than 5carbon atoms, for example the methyl radical.

As suitable optional additional substitutents P and Q in the naphthalenenucleus there may be mentioned, for example, halogen atoms, for examplechlorine or bromine atoms, or alkyl or hydroxy-alkyl radicals of notmore than 5 carbon atoms, for example the methyl or l-hyd-roxyet-hylradical, or acyl radicals, for example alkanoyl radicals of not morethan 6 carbon atoms, for example the acetyl radical, or sulphamoylradicals, optionally substituted, for example dialkylsulph-amoylradicals of not more than 10 carbon atoms, for example thedimethylsulphamoyl radical.

Particularly valuable naphthalene derivatives of the present inventionare, for example,

1-isopropylamino-3 1 n-aphthoxy) -2-propanol,

l-t-butylamino-3 1-naphthoxy)-2-propanol,

l-(2-hydroxy-1, l-dimethylethylamino) -3-( l-naphthoxy) .2-propano1.

l- 1-methyl-3-phenylpropylamino ),-3 l-naphthoxy) -2- prop-anol,

1-s-buty1amino-3 l-naphthoxy) -2 -propanol,

1-( l-methyloctyl-amino) -3 l-naphthoxy) -2-propanol,

. 3 1-( 1,1-dimethyl-3 -phenylpropylamino -3 -(1-naphthoxy) 2-propanol,l-allylamino-3 1-naphthoxy)-2-propanol, l-cyclopentylamino-S-(1-napthoxy)-2-propanol, l-isopropylamino-3 (4-methyll-naphthoxy)-2-propanol and 1- [3- (4-methoxyphenyl) -1-methylpropylamino]3lnaphthoxy -2-propanol,

and the esters thereof, and the salts thereof.

As suitable esters of the said naphthalene derivatives there may bementioned, for example, O-esters derived from acids of the formula R.COOH wherein R stands for an alkyl, alkenyl or aryl radical, optionallysubstituted, for example an alkyl or alkenyl radical of not more than 20carbon atoms or an aryl radical of not more than 10 carbon atoms, forexample the methyl, pentadecyl, hept-ade-cyl, heptadeca-S-enyl or phenylradical.

As suitable salts of the said naphthalene derivatives there may bementioned acid-addition salts, for example salts derived from inorganicacids, for example hydrochlorides, hydrobromides, phosphates, orsulphates, or salts derived from organic acids, for example oxalates,lactates, tartrates, acetates, salicylates, citrates, benzoates,naphthoates, o-acetoxybenzo'ates, adipates, maleates or1,1-methylene-bis-Z-hydroxy-3-naphthoates or salts with acidic syntheticresins, for example sulphonated polystyrene resins, for example Zeo-Karb225 (Zeo-Karb is a trademark). Relatively insoluble salts, for examplethe l,1'-methylene-bis-2-hyd-roxy-3-n-aphthoates are useful in that theyafford prolonged blood levels of the medicamerit.

According to a further feature of the invention we provide a process forthe manufacture of the naphthalene derivatives of the invention whichcomprises the interaction of a halogeno compound of the formula:

rivatives of the invention which comprises the interaction of an epoxideof the formula:

0.011 12 .CH-CHR whereinR R and R have the meanings stated above and thenaphthalene nucleus may optionally bear one or more additionalsubstituents, with an amine of the formula NHR R wherein R and R havethe meanings stated above.

This process may be carried out in a diluent or solvent, for exampleethanol, and it may be accelerated or completed by the application ofheat.

According to a further feature of the invention we provide a process forthe manufacture of the naphthalene derivatives of the invention whichcomprises the interaction of a naphthol derivative of the formula:

wherein R R R R R and X have the meanings stated above.

The interaction involving a naphthol derivative and a halogenoderivative may be conveniently carried out in the presence of anacid-binding agent; alternatively, an alkali metal derivative of thenaphthol derivative, for example the sodium or potassium derivative, maybe used as starting material.

According to a further feature of the invention we provide a process forthe manufacture of those of the naphthalene derivatives of the inventionwherein R stands for hydrogen and R stands for a radical of the formula--CHR' R wherein R stands for hydrogen or an alkyl, cycloalkyl, alkenyl,alkynyl, aryl or aralkyl radical, optionally substituted, and R standsfor an alkyl, cycloalkyl, alkenyl, alkynyl, aryl or aralkyl radical,optionally substituted, or wherein R and R are joined together with theadjacent carbon atom to form a cycloalkyl radical, optionallysubstituted, which comprises the interaction of an amino derivative ofthe formula:

QORERKCHOILCHRQNH;

wherein R R and R have the meanings stated above and the naphthalenenucleus may optionally bear one or more additional substituents, with acarbonyl compound of the formula R .CO.R wherein R and R have themeanings stated above, under reducing conditions.

Suitable reducing conditions are those provided by the presence ofhydrogen and a hydrogenation catalyst, for example platinum, in an inertdiluent or solvent, for example ethanol, and/or, in the case where, inthe said carbonyl compound used as starting material, R stands for analkyl, cycloalkyl, alkenyl, alkynyl, aryl or aralkyl radical, optionallysubstituted, in an excess of the carbonyl compound used as startingmaterial; or by the presence of an alkali metal borohydride, for examplesodium borohydride, in an inert diluent or solvent, for example aqueousmethanol, and/or in an excess of the carbonyl compound used as startingmaterial. It is to be understood that, in the case where R or R or bothstands or stand for an alkenyl or alkynyl radical, optionallysubstituted, if it is desired that this radical is not reduced to thecorresponding alkyl radical or substituted alkyl radical during thisprocess, suitable reducing conditions, for example those provided by theuse of sodium borohydride, must be used. It is to be further understoodthat the amino derivatives used as starting materials may be generatedin situ, for example by reduction of the corresponding a-diazoketone,a-azido-ketone and -alcohol, ahydroxyiminoketone, a-nitro-ketone and-alcohol, cyanhydrin or acyl cyanide.

According to a further feature of the invention we provide a process forthe manufacture of those of the naphthalene derivatives of the inventionwherein R stands for hydrogen, which comprises the hydrogenolysis of acompound of the formula:

wherein R R R and R have the meanings stated above, R stands for ahydrogenolysable radical, and the naphthalene nucleus may optionallybear one or more additional substituents.

As a suitable value for R there may be mentioned an a-aralkyl radical ofnot more than 10 carbon atoms, for

example the benzyl radical. The said hydrogenolysis may be effected bycatalytic hydrogenation, for example hydrogenation in the presence of aplatinum or palladiumon-carbon catalyst, conveniently in an inertdiluent or solvent, for example ethanol.

According to a further feature of the invention we provide a process forthe manufacture of those of the naphthalene derivatives of the inventionwherein the naphthalene nucleus bears as substituent a hydroxyalkylradical, which comprises the reduction of the corresponding compoundwherein the naphthalene nucleus bears as substituent the correspondingoxoalkyl radical. As a suitable oxoalkyl radical there may be mentioned,for example, an oxoalkyl radical of not more than 20 carbon atoms, forexample an alkanoyl radical of not more than 20 carbon atoms, forexample the acetyl radical. As a suitable reducing agent there may bementioned, for example, sodium borohydride.

According to a fiurther feature of the invention we provide a processfor the manufacture of the esters of the invention which comprises theacylation of the corresponding naphthalene derivative. As suitableacylating agents there may be mentioned, for example, acyl halides oracid anhydrides, for example acetic anhydride or benzoyl chloride. Theacylation may be carried out in a diluent or solvent, which, in the casewhere an acid anhydride is used, may conveniently be the acid from whichthe anhydride is derived.

According to a further feature of the invention we provide a process forthe manufacture of those of the naphthalene derivatives of the inventionwherein R stands for an alkanoyl radical, which comprises theisomerisation of an ester of the formula:

The isomerisation may be etfected by the interaction of the ester with astrong base, for example an alkali metal hydroxide, for example sodiumhydroxide, conveniently in a diluent or solvent, for example, methanol.

The invention is illustrated but not limited by the following examplesin which the par-ts are by weight:

Example 1 A mixture of 4.4 parts of l-chloro-3-(l-naphthoxy)- 2-propanoland 16 parts of isopropylamine is heated in a sealed vessel at 70-8(l C.for 10 hours. The vessel is cooled and to the contents there are addedparts of water. The mixture is acidified with 2 N-hydrochloric acid, andwashed with 50 parts of ether. The aqueous phase is decolourised withcarbon, and then added to 50 parts of 2 N-sodium hydroxide solution at 0C. The mixture is filtered. The solid residue is washed with water,dried, and crystallised from cyclohexane. There is thus obtained 1isopropylamino-El-(1-naphthoxy)-2-propanol, M.P. 96 C.

The above procedure is repeated using the appropriate chlorohydn'ns andamines as starting materials except that a reaction temperature of90'-l00 C. is used. In a similar manner there are obtained the compoundslisted in the following table. The hydrochlorides and oxalates listedare obtained by dissolving the base in ether, adding an etherealsolution of hydrogen chloride or oxalic acid, filtering the mixture,washing the solid residue with ether, and drying. The picrates listedare obtained by dissolving the base in ethanol, adding an ethanolicsolution of picric acid, filtering the mixture, washing the solidresidue with ethanol, and drying.

35 O.CR R .CH (0.0 OR .OHRiNIHR wherein R R R and R have the meaningsstated above Additional sub- M.P. Orystallisation R R stituents in naph-Base or salt C.) solvent (s) thalene nucleus t-Butyl Hydrogen oxalate..-230 Aqueous ethanol. 2-hydroxy-1,1di- Base 148 Ethanol.

iuethylethyl. Isobutyl Hydrochloride 166-168 Water. Isopropyl. 4-chloro.Hydrogen oxalate 186-188 Ethanol. Eth l Base 109-110 Cyclohexane.s-Butyl 60. 5-61 Hexane. Mlethyl methyl 82-83 P%% e(t3her, 0/. Methylisopropyl 120-122 Ethanol. H "I 2-hydroxyethy1 Base 84 Hexane.

R R Additional substituents Base or salt m.p. C.) Crystallisationnaphthalene nucleus solvent(s) Eth 157-158 Ethanol. 2-hydroxyethy1161-163 Do. H 3-morpholinopropyl. 89-91 Cyclohexane. H2-(3,4-di1nethoxy- Hydrogen oxalate... 209 Water/propanol.

phenyl) ethyl. H Isopropyl 4-methyl Base 90-91 Cyclohexane. H d5-din1et{1ylsulph- Hydro chloride i 190-193 lButanol.

amoy H Base Gyelohexane.

Hydrogen oxalate. -161 Ethanol. Hydrochloride 105-107 Ethyl acetate. -do169 Ethyl acetate/ethanol.

and R stands for an alkyl radical, for example an alkyl Example 2radical of not more than 5 carbon atoms, and wherein the naphthalenenucleus may optionally bear one or more additional substituents.

By the use of l-chloro-3-(2-naphthoxy)-2-propanol in place of the1-chloro-3-(l-naphthoxyl-Z-propauol used 7 in Example 1 there isobtained similarly l-isopropylamino-3-(2-naphthoxy)-2-propanol, M.P.138-140 C. (crystallised from ethanol).

By the use of t-butylamine in place of the isopropyloxalates andpicrates are obtained by the general procedures described in Example 1.

amine used in Example 2 there is obtained similarly l-t- 5O.OHZ.OHH.OH.NR R butylamino-3-(Z-naphthoxy)-2-propanol, M.P. 120 C.(from cyclohexane).

Position Additional substitof attachuents in naphtha- Reaction ReactionM.P. Orystallisation R R ment of lene nucleus temp. time Base or saltC.) solvent (s) main sub- 0.) (hours) stituent Ethyl..- Butyl 1 100 1Hydrogen oxalate... 100 Ethanollethylaceate. Z-hydrpxy-l-methyl- 1 100 1Base 115 Benzene.

ethy B-methoxy-propyl- 1 100 1 Hydrogen oxalate. 148-149 Propanol.2-(2-fbutoxyethoxy) 1 100 1 .....d0 138 Water.

at yl. 2-(2,4-dichloro- 1 100 1 Base 115 Pet. ehter, 100 C./

phen0xy)-ethyl. 120 C. 2-(4-en1orophenoxy) 1 100 1 Hydrogen oxalate...149-150 Water.

ethyl. 3-dimethylamino- 1 20 72 Dihydroehlorlde- 234-235 Methanol.

propyl. 1,1-dimethyl-3- 1 100 1 Oxalate 210-211 2-ethoxyethanol.phenylpropyl. l-methyl-Z-propy- 1 100 1 Plcrate 166-168 Propanol.

nyl. Isopropyl i 2-chloro 20 16 Hydrochloride 160-161 Ethanol/ethylaceate. do 1 4-acetyl 20 16 Base 95 Pet. etler, 100 C./ Isopropyl 12,4-dichloro 30 3 Hydrochloride. 194-195 Propanol/ethyl acetate. H.2-hydroxy-1,1-di- 2 None 100 1 Base 80-81 Pet. ether, 100 C./methyl-ethyl. 120 C. H Allyl 2 do 53 l Hydrochloride 182 Ethanol/ethylacetate.

Example 3 Example 5 A mixture of 2.3 parts of1-chloro-3-(1-naphthoxy)-2- propanol and 2.6 parts ofl-methyl-3-phenylpropylamine 35 is heated at 90100 C. for hours. Themixture is then cooled, diluted with 50 parts of Water, acidified with 2N-hydrochloric acid and filtered. The solid residue is shaken with 50parts of 2 N sodium hydroxide solution and 50 parts of ether. Themixture is separated, and the ethereal phase is dried over anhydrousmagnesium sulphate, filtered and evaporated. The residue is dissolveding 50 parts of ethyl acetate, and a solution of hydrogen chloride inether is added. The mixture is filtered, and the solid residue is washedwith ethyl acetate, dried, and crystallised from a mixture of methanoland ethyl acetate. There is thus obtained1-(-methyl-3-phenylpropylamino)- 3-(1-naphthoxy)-2-propanolhydrochloride, M.P. 162- 164 C.

Example 4 A mixture of 1.84 parts of 1,2-epoxy-3-naphthoxypropane and1.7 parts of isopropylamine is heated under reflux for 16 hours. Themixture is acidified with parts of 2 N-hydrochloric acid and Washed with50 parts of ether. The aqueous solution is then added to 50 parts of 2N-sodium hydroxide solution at 0 C., and the resulting mixture isfiltered. The solid residue is washed with Water, and dried, and thencrystallised from cyclohexane. There is thus obtained1-isopropylamino-3-(1-naphthoxy)-2- propanol, M.P. 96 C.

The base may be converted into the hydrochloride as follows:

4.65 parts of the base are dissolved in parts of Warm acetone. To thewarm solution there are added 2 parts of 10 N-hydrochloric acid. Themixture is allowed to cool, and is then filtered. The solid residue iswashed with acetone and then dried. The solid is crystallised frompropanol, and there is thus obtained1-isopropylamino-3-(lnaphthoxy)-2-propanol hydrochloride, M.P. 163 C.

The above procedure is repeated using the appropriateepoxy-naphthoxy-propanes and amines as starting materials, except thatvarious reaction temperatures and times are used in a similar mannerthere are obtained the compounds listed in the following table. Thehydrochlorides,

2.5 parts of 1-amino-3-(1-naphthoxy)-2-propanol hydrochloride is addedto a mixture of 100 parts of 2 N- sodium hydroxide solution and 200parts of ethylacetate. The mixture is shaken and separated. The ethylacetate layer is dried over anhydrous magnesium sulphate, filtered andevaporated. The residue is dissolved in parts of acetone, and 0.5 partof platinum oxide is added. The mixture is shaken at ambient temperatureand atmospheric pressure for 12 hours. The mixture is then filtered, andthe filtrate is evaporated to dryness under reduced pressure. Theresidue is dissolved in ethyl acetate, and ethereal hydrochloric acid isadded until no more solid is precipitated. The mixture is filtered. Thesolid residue is washed with ethyl acetate, and then dried. The solid iscrystallised from n-propanol and there is thus obtained1-isopropy1amino-3-( 1-naphthoxy)-2-propanol hydrochloride, M.P.163-164" C.

By using a mixture of 2.8 parts of heptyl methyl ketone and 40 parts ofethanol in place of the 80 parts of acetone there is obtained similarlyl-(l-methyloctylamino)-3-(1-naphthoxy) 2 propanol hydrochloride, M.P.116-118 C. (crystallised from ethyl acetate).

Example 6 A mixture of 2.5 parts of 2-bromo-4- (1-naphthoxy)- 3-butanoland 10 parts of isopropylamine is heated in a pressure vessel at C. for10 hours. The mixture is then evaporated under reduced pressure and theresidue is acidified with 25 parts of 2 N-hydrochloric acid. Carbon isadded, and the mixture is stirred and then filtered. The filtrate isadded to 50 parts of 2 N-sodium hydroxide solution, and the resultingmixture is then extracted with 50 parts of ether. The ethereal extractis dried over anhydrous magnesium sulphate, and then filtered and thefiltrate is acidified with ethereal hydrochloric acid. The resultingmixture is filtered, and the solid residue is crystallised from amixture of ethyl acetate and ethanol. There is thus obtained 2isopr0pylamino-4-(1-naphthoxy)-3-butanol hydrochloride, M.P. 210-212 C.

The 2-bromo-4-(1-naphthoxy)-3-butano1 used as starting material may beobtained as follows:

To a stirred solution of 3 parts of 2-bromo-4-(1- naphthoxy)-3-butanonein 20 parts of methanol at 5 C. there is added 0.5 part of sodiumborohydride. The mixture is stirred for 2 hours at C., and is thenpoured into 100 parts of ice. There are then added 50 parts of ether,and the resulting mixture is separated. The ethereal phase is dried overanhydrous magnesium sulphate and then evaporated. The residue consistsof 2- bromo-4-(1-naphthoxy)-3 butanol.2-bromo-4-(1-naphthoxy)-3-butanone itself may be obtained as follows:

To a stirred solution of 13 parts of diazoethane in 300 parts of etherat 10 C. there is added a solution of 10 parts of l-naphthoxyacetylchloride in 150 parts of ether. The mixture is stirred at 0 C. for 3hours, and then at ambient temperature for 18 hours. The mixture is thenstirred and cooled to -5 C., and 20 parts of 40% hydrobromic acid areadded. The mixture is stirred at 5 C. for 30 minutes. The mixture isseparated, and the ethereal phase is dried over anhydrous magnesiumsulphate. The mixture is filtered and the filtrate is evaporated underreduced pressure. The residue is extracted With 20 parts of cyclohexane,and the extract is filtered. The filtrate is evaporated under reducedpressure; the residue consists of 2-bromo-4-(1-naphthoxy)-3- butanone.

Example 7 A solution of 0.46 part of sodium in 20 parts of ethanol isadded to 2.42 parts of 1-chloro-3-(N-benzyl-N-isopropylamino)-2-propanol, and to this mixture 1.44 parts ofl-naphthol are added. The mixture is heated under pressure in a sealedtube at 100 C. during hours, and then evaporated to dryness underreduced pressure. The residue is stirred together with 50 parts of 2N-hydrochloric acid and 50 parts of ether. The mixture is separated andthe aqueous layer is basified by the addition of 2 N-sodium hydroxidesolution. The alkaline solution is extracted three times with 100 partsof ether. The combined ethereal extracts are Washed twice with 50 partsof water, dried over anhydrous magnesium sulphate, and the ether is thenremoved by distillation. There is thus obtainedl-N-benzyl-N-isopropylamino)-3-(1-naphthoxy)-2-propanol, which, by meansof the procedure described in Example 1, may be converted into apicrate, M.P. 157-8 C., containing one molecule of water ofcrystallisation (crystallised from aqueous dimethylformamide). The freebase may be regenerated from the purified picrate as follows:

2 parts of the picrate are suspended in 100 parts of ethyl acetate, andthis suspension is stirred together With 100 parts of 50% ammoniasolution. When all the picrate has dissolved, the resulting mixture isseparated. The organic layer is then extracted, each time with 50 partsof 50% ammonia solution, until the extracts are practically colourless.The ethyl acetate solution is then Washed twice with 50 parts of water,dried over anhydrous magnesium sulphate, and the ethyl acetate is thenremoved by distillation. There is thus obtained l-(N-benzyl-N-isopropylamino) -3-( 1-naphthoxy)-2-propanol.

Example 8 1 part of1-(N-benzyl-N-isopropylamino)-3-(1-naphthoxy)-2-propanol is dissolved in35 parts of ethanol. To the solution are added 2 parts of a saturatedethereal hydrogen chloride solution and 0.4 part of a palladium oncarbon catalyst. The mixture is shaken at ambient temperature andatmospheric pressure in an atmosphere of hydrogen until suflicienthydrogen has been absorbed to account for the hydrogenolysis of thebenzyl group, and no further uptake of hydrogen is occurring. Themixture is filtered and the filtrate is evaporated to dryness underreduced pressure. The residue is crystallised from n-propanol, and thereis thus obtained l-isopropylamino-3-( l-naphthoxy) 2-propanolhydrochloride, M.P. 163164 C.

10 Example 9 A mixture of 1.25 parts of l-amino-3-(1-naphthoxy)-2-propanol hydrochloride, 1.34 parts. of benzyl methyl ketone, 40 partsof ethanol and 0.1 part of platinum oxide is shaken in an atmosphere ofhydrogen at ambient temperature and atmospheric pressure until hydrogenabsorption ceases. The mixture is filtered and the filtrate isevaporated to dryness under reduced pressure. 25 parts of acetone areadded to the residue, and the resulting mixture is filtered. The solidresidue is washed with acetone, dried, and crystallised from a mixtureof ethanol and ethyl acetate. There is thus obtained 1(1methyl-2phenylethylamino) 3 (1-naphthoXy)-2- propanol hydrochloride, M.P. 186 C.

By using 1.25 parts of 2-(4-me-thoxyphenyl)-ethyl methyl ketone in placeof the 1.34 parts of benzyl methyl ketone there is similarly obtained1-[3-(4-methoxyphenyl)-1-methylpropylamino] 3 (1-naphthoxy)-2-propanolhydrochloride, M.P. 176178 C. (crystallised from ethanol).

By using 0.84 part of cyclopentanone in place of the 1.34 parts ofbenzyl methyl ketone there is similarly obtained 1-cyclopentylamino-3-(1 naphthoxy)-2-propanol hydrochloride, M.P. 208-209 C. (crystallisedfrom ethanol).

By using 2.5 parts of Z-heptadecanone in place of the 1.34 parts ofbenzyl methyl ketone there is similarly obtained 1-l-methylhexadecylamino -3-( 1-naphthoxy)-2- propanol hydrochloride, M.P.105106 C. (crystallised from ethyl acetate).

By using 1.36 parts of anisaldehyde in place of the 1.34 parts of benzylmethyl ketone there is similarly obtained 1(4-methoxybenzylamino)-3-(1-naphthoxy)-2-propano1 hydrochloride, M.P.190192 C. with decomposition (crystallised from ethanol).

Example 10 A mixture of 2 parts of 1,2-epoxy-3-(2-naphthoxy)- propaneand 5 parts of 1-methyl-3-phenylpropylamine is heated at 100 C. for 1hour. The mixture is then cooled and stirred together with 25 parts of 2N-hydrochloric acid and 50 parts of ether. The ethereal and aqueousphases are decanted, and the residue is crystallised from a mixture ofethanol and ethyl acetate. There is thus obtained1-(1-methyl-3-phenylp-ropylamino)-1-(2- naphthoxy)-2-propanolhydrochloride, M.P. 174-176 C.

Example 11 6.6 par-ts of 1-chloro-2-naphthol, 20 parts ofepichlorohydrin and 0.1 part of piperidine are refluxed together for 6hours. The mixture is then evaporated to remove unreactedepichlorohydrin. To the residue there are added 8 parts ofisopropylamine, and the mixture is heated under reflux for 10 hours. Themixture is then evaporated and the residue is heated together with partsof petroleum ether (B.P. 80100 C.). The solution thus obtained is cooledand filtered. The solid residue is washed with petroleum ether (B.P.80-100 C.) and dried, and is then crystallised from petroleum ether(B.P. 80-100" C.). There is thus obtained1-(1-chloro-2-naphthoxy)-3-isopropylamino-Z-propanol, M.P. 104 C.

By the use of 5 parts of 1-methyl-2-naphthol in place of the 6.6 partsof 1-chloro-2-naphthol there may be obtained in a similar manner1-isopropylamino-3-(l-methyl- 2-naphthoxy)-2-propanol, M.P. 122 C.[crystallised from petroleum ether (B.P. 80-100" 0.)].

Example 12 A mixture of 0.3 part of 3-bromo-1-(1-naphthoxy)-2- propanoland 5 parts of isopropylamine is heated in a sealed vessel at C. for 10hours. The vessel is cooled, and to the contents there are added 10parts of 2 N-hydrochloric acid. The mixture is filtered and the filtrateis basified with 2 N-sodium hydroxide solution and shaken together with25 parts of ether. The mixture is separated 1 l and the ethereal phaseis dried over anhydrous magnesium sulphate and then filtered. Thefiltrate is evaporated to dryness. The residue consists of1-isopropylamino-3-(lnaphthoxy)-2-propanol, M.P. 96 C.

The 3-bromo-1-(1-naphthoxy)-2-propanol used as starting material may beobtained as follows:

A solution of 0.28 part of 3-bromo-1-(1-naphthoxy) acetone and 5 partsof methanol is stirred and cooled to C. whilst 0.25 part of sodiumborohydride is added. The mixture is then stirred for a further 30minutes at 0 C. The mixture is then poured onto ice, acidified with 2N-hydrochloric acid and extracted with 20 parts of ether. The etherealextract is dried over anhydrous magnesium sulphate and filtered, and thefiltrate is evaporated to dryness. The residue consists of3-bromo-1-(1-naphthoxy)-2- propanol. It possesses a characteristicabsorption band in the infra-red at 3450 cmf 3-bromo-1-( l-naphthoxy)acetone itself may be obtained as follows:

A solution of 10 parts of l-naphthoxyacetyl chloride in 150 parts ofether is stirred and cooled to to C. whilst there is added during 30minutes a solution of 11 parts of diazomethane in 300 parts of ether.The solution is stirred for 2 hours at 5 C. and then for 18 hours atambient temperature. The solution is then stirred and cooled to 10 C.whilst there are added 20 parts of 11 N-hydrobromic acid. The mixture isthen stirred for minutes. The mixture is separated and the etherealphase is dried over anhydrous magnesium sulphate and filtered. Thefiltrate is evaporated to dryness, and the residue is crystallised fromcyclohexane. There is thus obtained 3-bromo-1-(1-naphthoxy)acetone, M.P.9294 C.

Example 13 A mixture of 8 parts of1-chloro-3-methyl-3-(l-naphthoxy)-2-butanol and parts of isopropylamineis heated in a sealed vessel at 100 C. for 10 hours. The excess ofisopropylamine, is evaporated and the residue is dissolved in 100 partsof N-hydrochloric acid. The solution is Washed with ether, and 20 partsof 8 N-sodium hydroxide solution are then added to the aqueous acidsolution. The mixture is extracted with 100 parts of ether and theethereal extract is washed with water and then dried with anhydrousmagnesium sulphate. The ethereal solution is evaporated to dryness. Theresidual gum is dissolved in 30 parts of ether, and ethereal hydrogenchloride is added until the precipitation of solid is substantiallycomplete. The mixture is filtered and the solid residue is crystallisedfrom a mixture of methanol and ethyl acetate. There is thus obtained 1isopropylamino-3-methyl 3 (l-naphthoxy)-2-butanol hydyrochloride, M.P.l38139 C.

The 1-chloro-3-methyl-3-(1-naphthoxy)-2-butanol used as startingmaterial may be prepared as follows.

A solution of 68 parts of a-(l-naphthoxy)-isobutyric acid in 450 partsof chloroform and 53 parts of thionyl chloride i heated under reflux for3 hours, and then the chloroform and the excess of thionyl chloride areevaporated. The residual gum is heated under reflux together with 600parts of petroleum ether (B.P. 6080 C.) and 5 parts of active carbon for15 minutes. The mixture is cooled to ambient temperature and thenfiltered. The filtrate is evaporated to dryness, and there is thusobtained a-( l-naphthoxy)-isobutyryl chloride as an oil.

A solution of 70 parts of a-(1-naphthoxy)-isobutyryl chloride in 200parts of other is treated with an excess of diazomethane in ether at 0C. for 24 hours, and then the ether and the excess of diazomethane areevaporated. The residual gum is dissolved in 250 parts of ether, andhydrogen chloride gas is passed into the solution at 0 C. until thesolution is saturated. The solution is stirred and 300 parts of ice areadded gradually. The mixture is separated and the ethereal solution iswashed successively three timeswith 100 parts of water each time, threetimes with 150 parts of 10% sodium carbonate solution each time andfinally three times with 100 parts of water each time. The

The process of Example 13 is repeated using 40 parts of t-butylamine inplace of 40 parts of isopropylamine.

There is thus obtained 1-t-butylamino-3-methyl-3-(1-naphthoxy)-2-butanol hydrochloride, M.P. 219-220 C.

Example 15 The procedure of Example 13 is repeated using 8 parts ofl-chloro-3-(1-naphthoxy)-2-butanol in place of 8 parts of l-chloro 3methyl-3-(1-naphthoxy)-2-butanol. There is thus obtained1-isopropylamino-3-(1-naphthoxy)- 2-butanol hydrochloride, M.P. 158159C.

The l-chloro-3-(1-naphthoxy)-2-butanol used as starting material may beobtained as follows:

A solution of 20 parts of a-(l-naphthoxy)-propionic acid in 300 parts ofchloroform and 16.5 parts of thionyl chloride is heated under reflux for3 hours, and then the chloroform and the excess of thionyl chloride areevaporated. The residual oil consists of ot-(l-naphthoxy-propionylchloride. A solution of 20 parts of this oil in parts of ether istreated with an excess of diazomethane in ether at 0 C. 'for 16 hours,and then the ether and the excess of diazomethane are evaporated. Theresidual gum is dissolved in parts of ether, and then hydrogen chloridegas is passed into the solution at 0 C. until the solution is saturated.The solution is stirred and 200 parts of ice are added gradually. Themixture is separated and the ethereal solution is washed successivelythree times With 50 parts of water each time, three times with 50 partsof 10% sodium carbonate solution each time, and finally three time with50 parts of water each time. The ethereal solution is dried withanhydrous magnesium sulphate and then evaporated to give chloromethyll-(lnaphthoxy)ethyl ketone, M.P. 7071 C. [crystallised from petroleumether (B.P. 6080 C.)].

15 parts of chloromethyl 1-(l-naphthoxy)-ethyl ketone are dissolved in200 parts of methanol, the solution is stirred at 0 C., and 7.5 parts ofsodium borohydride are added during 45 minutes. After 12 hours themethanol is evaporated and the residue is shaken together with 50 partsof ether and 30 parts of water. The mixture is separated, and theethereal solution is dried with anhydrous magnesium sulphate and thenevaporated to dryness. There is thus obtained l-chloro-3-(1-naphthoxy)-Z-butanol as an oil.

Exiample 16 A solution of 1.25 parts of 1-isopropylamino-3-(1-naphthoxy)-2-propanol and 1 part of acetic anyhydride in 10 parts ofacetic acid is kept at ambient temperature for 18 hours, and is thenadded to a mixture of 50 parts of ice and 10 parts of 11 N-ammoniumhydroxide solution. The aqueous phase is decanted, and as much aspossible of the residue is dissolved in 2 N-hydrochloric acid at 0 C.The solution is basified with 2 N-sodium hydroxide solution and thenextracted with 50 parts of ether. The ethereal extract is dried overanhydrous magnesium sulphate, and filtered. To the filtrate there isadded a saturated solution of oxalic acid in ether until precipitationis substantially complete. The mixture is filtered and the solid residueis crystallised from ethanol. There is thus obtained 1isopropylaminome'thyl-2-( l-naphthoxy-ethyl acetate as its hydrogenoxalate, M.P. 202204 C.

In place of the oxalic acid there may be used hydrogen chloride and in asimilar manner there is obtainedl-isopropylaminomethyl-2-(1-naphthoxy)-ethyl acetate as itshydrochloride, M.P. 170l71 C. (crystallised from a mixture of ethanoland ethyl acetate).

Example 17 A mixture of 2.95 parts of1-isopropylamino-3-(lnaphthoxy)-2-propanol hydrochloride and 6 parts ofbenzoyl chloride are heated at 100 C. for 6 hours. The mixture iscooled, and there are then added 50 parts of ether. The mixture is keptat ambient temperature for 3 days and is then filtered. The solidresidue is washed with ether, and crystallized from 25 parts of benzene.There is thus obtained 1-isopropylaminomethyl-2-(l-naphthoxy) ethylbenzoate as its hydrochloride, M.P. 130132 C.

Example 18 2 parts of sodium borohydride are added during 10 minutes toa stirred solution of 2 parts of 1-(4-acetyl-1-naphthoxy)-3-isopropylamino-2-propanol in 80 parts of methanol at C. Themixture is stirred at 0 C. for 1 hour and then poured onto 100 parts ofice, acidified with 2 N-hydrochloric acid, and filtered. The filtrate isbasified with 2 N-sodium hydroxide solution and extracted with 500 partsof ether. The ethereal extract is dried over anhydrous magnesiumsulphate and then filtered. To the filtrate there is added a saturatedsolution of oxalic acid in ether until precipitation is substantiallycomplete. The mixture is filtered, and the solid residue is crystallisedfrom a mixture of ethanol and ether. There is thus obtained 1 (4a-hydroxyethyl-1-naphthoxy)-3-isopropylamino-Z-propanol hydrogenoxalate, M.P. 146-147 C. with decomposition.

Example 19 A solution of 0.77 part of l-isopropylaminomethyl-Z-(l-naphthoxy)-ethyl acetate hydrochloride in 16 parts of methanol istreated with 3.5 parts of N-sodium hydroxide at ambient temperature, andafter 1 hour the methanol is evaporated under reduced pressure. Theresidue is shaken together with 20 parts of ether and 10 parts ofN-hydrochloric acid. The mixture is separated and the ethereal solutionis washed with water, dried over anhydrous magnesium sulphate and thenevaporated to dryness. The residue is crystallised from a mixture ofacetate and light-petroleum (B.P. 40-60 C.), and there is thus obtainedN acetyl 1 isopropylamino-3-(l-naphthoxy)-2-propanol, M.P. 91 C.

Example 20 A solution of 29.5 parts of 1-isopropylamino-3-(1-naphthoxy)-2-propanol hydrochloride in 300 parts of water is added to asolution of 43.2 parts of disodium 1,1 methylene bis(2-hydroxy-3-naphthoate) in 4000 parts of water. The mixture is filteredand the solid residue is washed with water and dried. The solid iscrystallised from ethanol, and there is thus obtained di- [1isopropylamino 3-(l-naphthoxy)2-propanol] 1,1-methylenebis-(2-hydroxy-3-naphthoate), M.P. 212 C.

Example 21 A solution of 1.3 parts of 1-isopropylamino-3-(1-naphthoxy)-2-propanol in 25 parts of ethyl acetate is added to asolution of 0.7 part of benzoic acid in parts of ether. The mixture isfiltered and the solid residue is washed with ether and dried. There isthus obtained 1 isopropylamino-3-(1-naphthoxy)-2-propanol benzoate, M.P.143144 C. (crystallised from Water).

By substituting 0.96 part of fi-naphthoic acid for the 0.7 part ofbenzoic acid there is similarly obtained l-isopropylamino3-(1-naphthoxy)-2-propanol fi-naphthoate, M.P. 132 C. (crystallised froma mixture of cyclohexane and ethanol). I

naphthoxy) -2-propanol,

By substituting 0.98 part of O-acetoxybenzoic acid in place of the 0.7part of benzoic acid there is similarly obtained1-isopropylamino-3-(l-naphthoxy)-2-propanol O- acetoxybenzoate, M.P.l22124 C. (crystallised from ethyl acetate).

By substituting 0.7 part of adipic acid in place of the 0.7 part ofbenzoic acid there is similarly obtainedl-isopropylamino-3-(.1-naphthoxy)-2-propanol adipate, M.P. -147 C.(crystallised from a mixture of ethyl acetate and ethanol).

By substituting 0.6 part of maleic acid in place of the 0.7 part ofbenzoic acid there is similarly obtainedl-isopropylamino-3-(1-naphthoxy)-2-propanol maleate, M.P. 145-146 C.(crystallised from a mixture of ethyl acetate and ethanol).

By substituting 0.62 part of oxalic acid in place of the 0.7 part ofbenzoic acid there is similarly obtained 1- isopropylamino 3 (1naphthoxy)-2-propanol oxalate, M.P. -182 C. (crystallised from a mixtureof methanol and ethyl acetate).

Example 22 To a stirred solution of 10 parts of l-isopropylamino-3-(l-naphthoxy)-2-propanol hydrochloride in 100 parts of Water there isadded a suspension of 100 parts of a sulphonated polystyrene resin[Zeo-Kar 225 (SCR) 3)-- Zeo-Karb is a trademark] in the sodium form in400 parts of water. The mixture is stirred for 60 minutes at ambienttemperature and is then filtered. The solid residue is washed with waterand dried at ambient temperature. There is thus obtained a complex saltof l-isopropy1amino-3-(1-naphthoxy)-2-propanol With the sulphonatedpolystyrene resin which has a base content of 9%.

What we claim is:

1. A compound selected from the group consisting of naphthalenederivatives of the formula:

wherein R is selected from the group consisting of branchedchain alkylof not more than 20 carbon atoms, cycloalkyl of not more than 5 carbonatoms, ethyl, hydroxy-branched-chain-alkyl of not more than 4 carbonatoms, alkoxyalkyl and dialkylaminoalkyl of not more than 5 carbonatoms, allyl, phenylbranched-chain alkyl of not more than 15 carbonatoms and monoand di-alkoxyphenyl alkyl of not more than 15 carbonatoms; and

and Q are selected from the group consisting of hydrogen, chlorine,bromine and alkyl and hydroxyalkyl of not more than 5 carbon atoms, andacetyl and dimethylsulphamoyl, one of said substituents P and Q beinghydrogen when the other is acetyl or dimethylsulphamoyl; andpharmaceutically-aoceptable acid-addition salts thereof.

2. A compound claimed in claim 1 which is selected from the groupconsisting of 1-isopropylamino-3-(l-naphthoxy)-Z-propanol,1-t-butylamino-3 (1-naphthoxy)-2- propanol, 1-(2hydroxy-1,ldimethylethylamino)-3-(1- naphthoxy)-2 propanol, l-(1-methyl-3phenylpropylamino)- 3 -(l-naphthoxy)-2-prop-anol, 1-s-butylamino-3-1-naphthoxy)-2-propanol, 1-( l-methyloctylamino) -3 1- 1-( 1,1-dimethyl3-phenylpropylamino) -3-( l-naphthoxy) -2-propanol,1-allylamino-3-( 1- naphthoxy)-2-propanol, l-cyclopentylamino3-(1-naphthoxy) -2-propanol and 1-[3-(4-methoxyphenyl) -1-meth-3,337,623 15 16 ylpropylamino] 3-(1-naphthoxy) 2-propanol, and the OTHERREFERENCES pharmaceutically-acceptable acid-addition salts thereof.Beasley 6t 1 101m Pharm Pharmacoh VOL 3. 1-is0propy1-amino-3-( l-naphthoxy) -2-propan01. 47 5 9 (1958).

Ing et a1.: J our. Pharm. PharmacoL, v01. 4, pp. 21-6 References Cited 5(1952). UNITED STATES PATENTS PCtIOW 61 211.1 1011f. Pharm. PharmacoL,V01. 8, pp.

666-75 (1956). 3,033,640 5/1962 Hofer et a1. 260 -570.7 XR

CHARLES B. PARKER, Primary Examiner.

10 HENRY R. JILES, Examiner.

J. TOVAR, R. V. HINES, Assistant Examiners.

FOREIGN PATENTS 1,198,123 12/195-9 France.

622,297 4/1949 Great Britain.

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF NAPHTHALENE DERIVATIVES OF THE FORMULA: 